Our recent findings of robust neurovascular protection with early blood pressure (BP) lowering after stroke has prompted us to, in this competitive renewal, continue to elucidate mechanisms of the protective effects of BP management in the hours after stroke. Our long term goal is to understand the pathways of neurovascular injury in the brain during and after ischemic stroke in order to design and implement better treatments for stroke patients. In the first funding period, we determined that BP lowering after reperfusion is neurovascularprotective, and the best outcomes are achieved when angiotensin blockade is employed. The central hypothesis for the proposed research is that vascular protection, accomplished by early BP lowering, activates endogenous survival proteins, including those of the antiapoptosis and angiogenic pathways, even without reperfusion. We plan to test our central hypotheses and accomplish the overall objectives of this application through the following specific aims: Specific Aim #1: Determine the extent to which recovery after cerebral ischemia and BP lowering is dependent upon the presence and method of reperfusion. Our working hypothesis is that the neurovascular protective effect of early BP lowering persists whether or not reperfusion is achieved, mechanically or by thrombolysis. Specific Aim #2: Determine the extent to which early BP lowering after cerebral ischemia induces endogenous survival pathways. Our working hypothesis is that early BP lowering induces a post conditioning- like state that results in persistent vascular protection, leading to recovery. This protection is reliant on antiapoptotic Akt and proangiogenic VEGF activation. PUBLIC HEALTH RELEVANCE: Project Narrative: Relevance to Veterans Health: Central nervous system injury and related disorders is a stated area of priority in the VA health care mission. Stroke is a leading cause of death and disability in VA patients and is very costly to the VA system. Strategies to achieve effective treatment of stroke have the potential for a large impact on VA patients and their families. This project is both mechanistic and translational in that the results will be used to design a clinical trial in stroke patients.